tbuckley/cabot-search huggingface dataset:
Psychosocial, behavioral, and communication factors associated with completion of the mt-sDNA test for colorectal cancer screening.
Authors: Shama Alam, Xuan Zhu, Linda Squiers, Leah Helmueller, Gabriel Madson, Brian Southwell, Carlye Gates, Bonny Kneedler, Paul J. Limburg, Lila J Finney Rutten
Journal: Journal of Clinical Oncology (2023)

60 Background: Colorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality. Several CRC screening modalities are guideline recommended for average-risk adults aged 45-75 years. CRC screening is underutilized in the US and access to facility-based options, such as colonoscopy, represents a potential barrier. Home-based stool tests are guideline-endorsed and offer a convenient, accessible, scalable option for CRC screening. Thus, understanding the factors that influence completion of stool-based CRC screening is important to guide interventions to improve adherence. We developed a survey, informed by behavioral theory, to identify psychosocial, behavioral and communication factors associated with completion of mt-sDNA screening. Methods: The survey instrument was finalized through expert review, quality testing, and cognitive testing. Adults aged 45-75 years, with a US postal address, who received a valid order for mt-sDNA and whose kit was shipped between 5/21-9/21 were eligible for sampling. RTI administered the survey between 3/22-6/22. Participants had the option to complete electronic or paper surveys. We fit a multivariable logistic regression to identify factors significantly associated with mt-sDNA test completion. Results: Of 17,370 individuals invited to participate, 2,973 completed the survey (AAPOR RR3 = 21.7%); 77.3% of the sample completed the mt-sDNA test. Responders and non-responders did not differ significantly by sex or age. Controlling for demographic characteristics and insurance status, the odds of mt-sDNA test completion were significantly higher among participants who reported greater perceived test effectiveness (OR = 1.20), greater ease (OR = 4.06), and greater comfort in test use (OR = 1.18). Odds of test completion were significantly higher among participants who reported their healthcare provider discussed the mt-sDNA test with them (OR = 2.01) and involved them a great deal in decision making about CRC screening (OR = 1.29). Participants who expressed greater worry about developing CRC were less likely to return their mt-sDNA kit (OR = 0.81). Conclusions: To improve population adherence to CRC screening recommendations, efforts are needed to ensure patients understand the attributes and effectiveness of available test options and feel adequately prepared to complete their preferred screening test. Additionally, healthcare providers must be appropriately prepared and resourced to educate and to engage patients in shared decision-making about CRC screening.
Trends in pancreatic cancer incidence and mortality in the United States from 2000 to 2019: A SEER-based study.
Authors: Oluseyi Abidoye, Young Min Cho, Ange Ahoussougbemey Mele, Sheena Bhushan, Ruben Ruiz Vega, Aditya Kumar Ghosh
Journal: Journal of Clinical Oncology (2023)

755 Background: The annual incidence and mortality rates of pancreatic cancer has been rising. We analyzed pancreatic cancer trends by demographics and geographic location. Methods: Data obtained from the Surveillance, Epidemiology, and End Results (SEER) registry 17 were available to assess trends of pancreatic cancer incidence and mortality from 2000 to 2019. Results: The pancreatic cancer incidence and mortality rates consistently increased over time from 2000 to 2019. Incidence of pancreatic cancer was highest in males (14; 95% Cl, 13.9,14.1) and blacks (15.4 95% Cl,15.2, 15.6). The incidence was highest in Alaska (16.2; 95% Cl, 14.1, 18.5), and lowest in Utah (10.7; 95% Cl, 10.4, 11.0). Incidence increased at 0.85% per year (95% Cl, 0.76, 0.92; P &lt; .001). Overall incidence increased significantly for all sex, race, stage sub-groups except for Blacks (APC of 0.04%; 95% Cl, -0.14, 0.22; P = 0.649), and American Indian/Alaska natives (APC of -0.22 %; 95% Cl, -1.33, 0.89; P = 0.679). There was an overall significant increase in incidence across all states except for Alaska. Incidence-based mortality of pancreatic cancer was highest in males (12.6; 95% Cl, 12.5,12.7) and blacks (14.1; 95% Cl, 13.9, 14.3). Mortality was highest in Alaska (15.1; 95% Cl, 13.1,17.3), and lowest in Utah (9.6; 95% Cl, 9.3,9.9). Mortality increased at 0.91% per year (95% Cl, 0.32, 1.50; P = .005). The overall incidence-based mortality increased significantly only in the males APC, 0.95% (95% Cl, 0.36, 1.54; P = 0.003), females APC 1.18 (95% Cl, 0.47, 1.89; P = 0.002) and whites APC 1.05% (95% Cl, 0.45, 1.66; P = 0.002). Furthermore, there was an overall significant increase in incidence-based mortality across all states except for Alaska, Hawaii and Washington. Conclusions: Pancreatic cancer incidence and mortality rates increased overall but differed by demographics and geographic location.
Racial/ethnic differences of germline pathogenic variants in cancer susceptibility genes among patients with early-onset colorectal cancer.
Authors: Andreana N Holowatyj, Hannah M Seagle, Samantha Keller, Sean V Tavtigian, David E Goldgar, Carolyn Horton
Journal: Journal of Clinical Oncology (2023)

19 Background: The burden of early-onset colorectal cancer (CRC diagnosed before age 50 years) differs across racial/ethnic groups. Yet the distinct prevalence and spectrum of germline pathogenic variants associated with early-onset CRC by race/ethnicity is uncharacterized. Methods: We identified 3,980 early-onset CRC patients unselected for family CRC history who underwent clinical multi-gene panel testing of 14 CRC susceptibility genes ( MLH1, MSH2, MSH6, PMS2, SMAD4, APC, BMPR1, CHEK2, EPCAM, MUTYH, PTEN, STK11, CDH1, and TP53) performed by a nationwide clinical testing laboratory from 2012 to 2016 and identified as Ashkenazi Jewish, Asian, Black, Hispanic, or White. Multi-gene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis. Clinical and individual/family histories were ascertained from clinician-completed test requisition forms. Germline variant prevalence and spectrum in early-onset CRC was determined by race/ethnicity. Pathogenic variant comparisons by race/ethnicity were evaluated using chi-square tests and multivariable logistic regression adjusted for sex, age, CRC site and sequence. Results: Among 3,980 early-onset CRC patients, a total of 503 germline genetic variants were identified in 481 individuals (12.1%). By race/ethnicity, 12.7% of Ashkenazi Jewish, 8.6% of Asian, 10.3% of Black, 14.0% of Hispanic, and 12.3% of White individuals presented with a pathogenic variant in a CRC susceptibility gene. Nearly 7% of early-onset CRC patients (n = 268) presented with a germline pathogenic mutation in a mismatch repair gene—with the prevalence of Lynch Syndrome in early-onset CRC differing across racial/ethnic groups ( P= 0.037). The prevalence of germline APC, CHEK2, MLH1, monoallelic MUTYH, and PTEN variants also varied by race/ethnicity (all P&lt; 0.02). Overall, Asian individuals with early-onset CRC had 49% lower odds of carrying a pathogenic germline variant in a CRC susceptibility gene versus White individuals in adjusted models (Odds Ratio [OR] = 0.51, 95% Confidence Interval [CI]: 0.26-0.99, P= 0.046). Ashkenazim and Hispanic individuals had higher odds of presenting with pathogenic APC and MLH1 variants, respectively, compared with White individuals in adjusted models ( APC: OR = 8.69, 95% CI: 2.68-28.21, P= 0.0003; MLH1: OR = 2.67, 95% CI: 1.30-5.49, P= 0.007). Conclusions: Of 3,980 patients with early-onset CRC unselected for family history, the prevalence and spectrum of pathogenic germline variants differed across racial/ethnic populations. Beyond multigene panel testing for all early-onset CRC patients, further study is needed to optimize genes selected for germline genetic testing in early-onset CRC across diverse groups—which would have clinical implications for disease surveillance and intervention.
The identification of reversion mutations in patients with advanced pancreatic cancer and germline or somatic <i>BRCA</i> or <i>PALB2</i> variants who were treated with maintenance rucaparib.
Authors: Timothy J Brown, Arielle Yablonovitch, Jennifer Yen, Lesli A. Kiedrowski, Erica L. Carpenter, Katherine Nathanson, Susan M. Domchek, Kim Anna Reiss
Journal: Journal of Clinical Oncology (2023)

734 Background: Maintenance PARP inhibition (PARPi) extends progression-free survival and improves quality of life for patients (pts) with advanced, platinum-sensitive pancreatic cancer (PC) and BRCA or PALB2 variants. However, most will experience progression. PARPi resistance mechanisms are poorly defined in PC. Cell-free (cf)DNA analysis can detect some known classes of resistance mechanisms, like reversion mutations, and other potentially prognostic and predictive genomic features. Methods: Pts with advanced, platinum-sensitive pancreatic cancer and pathogenic germline or somatic BRCA1, BRCA2, or PALB2 variants were treated with maintenance rucaparib on clinical trial. cfDNA was collected at baseline and progression and analyzed with the GuardantOMNI 500-gene liquid biopsy. Time to event analysis was performed from index date of enrollment until endpoint (PFS, OS, and PFS2). Associations were tested by the log-rank test with adjustment. Results: The trial enrolled 42 pts, of whom 31 have progressed. cfDNA was available for 41 pts at baseline and 30 pts at progression; 88% had baseline detectable cfDNA. Two pts had baseline reversion mutations, 5 had new reversion mutations at progression. Of 21 pts who had tissue NGS, 17 pts had a KRAS variant in the tumor, 12 of whom had detectable cfDNA at either baseline or progression. Of the 41 patients with cfDNA samples, 10 pts had baseline KRAS mutations detected in plasma; an additional 10 pts had a detectable plasma KRAS mutation at progression. Outcomes are shown. Of those who had progressed, pts with acquired reversion mutations had shorter OS (p&lt;0.001) and PFS (p = 0.018) on rucaparib than those without reversion mutations. Of those who received chemo after progression (n=23), PFS2 was shorter for pts with acquired reversions compared to those with no reversions (p = 0.038). KRAS mutation detection at baseline was observed with higher overall somatic allele fraction in cfDNA and a trend toward shorter PFS and OS. Conclusions: Acquired reversion mutations were infrequent but associated with worse outcomes. Other causes of resistance may be dominant. Detection of KRAS mutation in the peripheral blood may be associated with disease burden and clinical outcome. [Table: see text]
Age- and sex-based differences in the genomic profiles of patients with gastrointestinal (GI) and pancreatic neuroendocrine neoplasms (NENs).
Authors: Lisa Liu, Shuning Li, Nishant Gandhi, Alex Patrick Farrell, Emil Lou, Heloisa P. Soares, Bassel Nazha, Jeffrey Swensen, Matthew James Oberley, Chadi Nabhan, Jim Abraham, Wolfgang Michael Korn, Pamela L. Kunz, Namrata Vijayvergia
Journal: Journal of Clinical Oncology (2023)

655 Background: Demographic variables such as age and sex have long been associated with risk of cancer incidence, therapeutic response, and mortality. In NENs, specifically, studies have shown differences in overall survival based on age at diagnosis and sex. However, studies investigating the molecular determinants associated with age and gender have been lacking. To delineate the mechanisms of age, gender, and outcomes, we queried a large real-world dataset of NENs originating from the GI-tract and pancreas and characterized their molecular and immune profiles. Methods: 1935 cases (GI: n=1431, Pancreas: n=504) of NENs were analyzed using Next Generation Sequencing or Whole Exome Sequencing of DNA, and 1211/1935 cases (GI: n=917, Pancreas: n=294) underwent Whole Transcriptome Sequencing at Caris Life Sciences (Phoenix, AZ). To study the age-associated effect on the molecular and immune landscapes, we applied two age cutoffs: below 50 and 70 years of age at the time of tissue collection, respectively. Significance was determined using chi-square, Fisher-Exact or Mann-Whitney U, and p-values were adjusted for multiple comparisons (q&lt;0.05). Results: In GI-NEN, TP53, RB1 mutations and high tumor mutation burden (TMB_H; &gt;=10 Mut/Mb) were more prevalent and KRAS mutations were less prevalent with increasing age. Interestingly, in pancreatic NENs (P-NENs), KRAS mutations were more prevalent and TMB_H were less prevalent with increasing age. Mutations specific to the sites of origin such as APC (GI) and MUTYH (pancreas) were negatively associated with age while SMAD4 (pancreas) was positively associated with age. While no differences in immune checkpoint gene (ICG) expression were associated with age, immune cell estimates of M1 macrophages (anti-tumorigenic) in GI-NENs were higher in patients above 70 and M2 macrophages (pro-tumorigenic) were higher in patients below 50 (p&lt;0.05, q&gt;0.05). For the analysis with gender, mutations in p53 were more prevalent among males with GI-NEN while dMMR/MSI-H were more prevalent in females with P-NENs. No significant differences in ICG expression and immune cell estimates were associated with gender. Conclusions: Our study queries one of the largest datasets of GI and P-NENs to date. We observe distinct molecular profiles associated with age and gender in both GI- and P-NENs as well as a distinct immune profile associated with age in GI-NENs. While these results are only hypothesis generating, they are suggestive of how patient demographics may be utilized for rational therapy design. [Table: see text]
Prevalence of UGT1A1 polymorphisms in gastrointestinal cancer: A single-institutional retrospective study.
Authors: Bei Jiang, Nour Daboul, Maria Hafez, Sijin Wen, Crystal Heise, Danish Safi, Abdulrahman Abonofal, Emma Uchida, Midhun Malla
Journal: Journal of Clinical Oncology (2023)

797 Background: UGT1A1 gene polymorphisms are heterogeneously distributed among ethnicities and varying geographical regions. Patients with UGT1A1*6 and UGT1A1*28 polymorphisms have an increased risk of grade 3-4 neutropenia and diarrhea from irinotecan due to poor metabolism. This study evaluated the prevalence of UGT1A1 polymorphisms in the cancer patients in a large tertiary cancer center in the Appalachian region, in order to develop individualized institutional guidelines on the utility of UGT1A1 testing in chemotherapy dose management. Methods: This retrospective study evaluated all patients with gastrointestinal (GI) malignancies who underwent UGT1A1 testing prior to chemotherapy initiation between 1/1/2020 and 6/30/2022 at West Virginia University. All patients within this disease sub-specialty who were eligible for chemotherapy were tested for UGT1A1 *6 and UTG1A1*28 polymorphism via PCR based pharmacogenomic evaluation using OneOme RightMed comprehensive testing. Patients were excluded if they were tested for genetic alterations specifically due to previous treatment intolerances. Prevalence of the alterations along with demographic characteristics of patients are reported. Results: UGT1A1 genotyping was performed in 278 patients prior to initiating chemotherapy and 12 patients were excluded due to insufficient sample. A total of 266 patients met the inclusion criteria. The median age was 66 years (IQR: 26-92). Males constituted a higher proportion of the population compared to females (M: F = 147: 119). Colon (n-81; 30.5%) and pancreatic (n-80; 30%) cancers were the predominant GI malignancies. Fifty five percentage of patients (n-146) had metastatic disease. The distribution of the UGT1A1 variant genotype is showed in the table below. Conclusions: The prevalence of heterozygous and homozygous of UGT1A1*28 polymorphism in GI cancer patients in the Appalachian region is 51.5%, consistent with the reported literature. Homozygous and heterozygous UGT1A1 *28 alterations constituted 13.2 and 38.3% respectively. Data collection for pre-emptive chemotherapy dosage adjustments and adverse events is ongoing to integrate testing for UGT1A1 polymorphism routinely for all GI malignancies cancer patients starting irinotecan chemotherapy.[Table: see text]
CD34 immunostaining for microvascular invasion analysis in hepatocelullar carcinoma.
Authors: Paulo Henrique Costa Diniz, Henrique Valladao Pires Gama, Ronniel Morais Albuquerque, David Campos Wanderley, Marcelo Xavier, Fernanda Maria Farage Osorio, Claudia Alves Couto, Teresa Cristina de Abreu Ferrari, Agnaldo Soares Lima, Gabriela Freitas Chaves, Paula Vieira Teixeira Vidigal
Journal: Journal of Clinical Oncology (2023)

609 Background: Hepatocellular carcinoma is the most common primary neoplasia of the liver. Microvascular invasion predicts outcome and defines tumor staging. However, its diagnosis is still a challenge. The present study aims to evaluate inter and intraobserver agreement in identifying the presence of microvascular invasion using conventional and immunohistochemistry histology. Methods: Three pathologists performed the analysis of 76 hepatocellular carcinoma explants to characterize the presence of microvascular invasion using the hematoxylin/eosin stain and immunohistochemistry for CD34. The evaluations were made individually, in two distinct moments. Results were analyzed by the Kappa’s coefficient and ROC curves. Results: Our study demonstrated similar agreement for microvascular invasion between hematoxylin/eosin and CD34 methods. However, the intraobserver agreement values for both methods were higher than the interobserver ones. The accuracy of CD34 in relation to hematoxylin/eosin by ROC curves in intraobserver analysis tends to a high specificity, ranging from 82.1 to almost 100%, with sensitivity of 46.9 to 81.1%. In interobserver analysis, CD34 also has a high specificity (84.3 to 85.5%) while its sensitivity is a little shorter (81.2 to 84.3%). Conclusions: Intraobserver higher agreement allows us to suppose that pathologists employed own criteria to evaluate vascular invasion, reinforcing the need of standardization. ROC Curves analysis showed that the CD34 method is more specific than sensitive. Therefore, immunohistochemistry for CD34 should not be used routinely, but it could be useful to help confirming invasion previously seen by conventional histology.
Comparison of precursor neoplasms at colonoscopic diagnosis of early-onset and later-onset colon cancer.
Authors: Oluwadunni Eunice Emiloju, Bahar Saberzadeh Ardestani, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2023)

74 Background: Colorectal cancer (CRC) incidence has steadily increased in adults younger than 50 years (EO-CRC) since the 1990s, with a reported higher prevalence in the left colon and rectum. Established precursor lesions of CRCs are adenomas, including advanced adenomas, and sessile serrated polyps. We hypothesized that patients at diagnosis of early-onset colon cancer (EO-CC) would have fewer adenomas compared to patients with later-onset colon cancer (LO-CC). Methods: We performed a retrospective review of electronic health records and identified 58 patients diagnosed with EO-CC who had colonoscopy at Mayo Clinic or Mayo Health System who were then matched with 58 LO-CC patients based on gender and procedure indication (diagnostic in 76%, surveillance 16%, screening 8%)[2012 to 2021]. At colonoscopy where colon cancer was diagnosed, we recorded findings of adenomas, advanced adenomas (≥ 1 cm, villous histology, and/or high-grade dysplasia) and sessile serrated polyps. On CCs, limited molecular data were available [mismatch repair (MMR); BRAF V600E , KRAS]. Results: Among 116 patients included in the EO-CC and LO-CC study arms, the median age at cancer diagnosis were 42 and 74 years, respectively. No significant differences were found between study arms and risk factors for CRC including tobacco, alcohol, BMI, genetic syndromes, family history of CRC, and MMR, BRAF V600E or KRAS status (all p&gt; 0.05). While no difference was found for polyp number by arm, patients with EO-CC had larger polyps (median of 10 mm vs 6 mm, p=0.001) compared with LO-CC. At least 1 adenoma was found in 50% and 52% of patients with EO-CC and LO-CC, respectively. Importantly, advanced adenomas were significantly more common in the EO-CC group compared with the LO-CC group (41% and 21%, p=0.027). Sidedness of all adenomas did not differ significantly for EO-CC vs LO-CCs. Conclusions: Patients found to have a primary EO-CC had a significantly higher likelihood of a synchronous advanced adenoma in the colon compared to those with a primary LO-CRC. Together, these data suggest accelerated carcinogenesis throughout the colorectum with increased risk of synchronous and metachronous patients with EO-CC. [Table: see text]
The association between KRAS mutational status, clinicopathological factors including the preoperative systemic inflammatory response and outcomes in TNM stage I-III colon cancer.
Authors: Allan Matthew Golder, Kathryn AF Pennel, David Mansouri, Paul G. Horgan, Campbell SD Roxburgh, Andrew V Biankin, Joanne Edwards, Donald C. McMillan
Journal: Journal of Clinical Oncology (2023)

193 Background: TNM Stage is the most significant prognostic indicator in colon cancer however other tumour and host factors (eg the systemic inflammatory response (SIR)) are associated with long-term outcomes. The relationship between the tumour and the host SIR remains poorly understood. KRAS mutations are associated with adverse outcomes in metastatic disease and have been reported to have an inflammatory phenotype however this has not been widely studied in non-metastatic disease. The present study investigates the association between KRAS mutations, clinicopathological factors including the SIR and outcomes in TNM I-III colon cancer. Methods: Two cohorts of patients (single centre–2000-2008 and regional-2011-2014) undergoing curative surgery for TNM I-III colon cancer in the West of Scotland were shown to be well-matched and combined. Mutational status was analysed retrospectively. The SIR was stratified using Systemic Inflammatory Grade (SIG). 3-year overall and cancer specific survival (OS and CSS) were measured from date of surgery until date of death. Results: 267 patients were identified, 45% with KRAS mutations. KRAS mutations were associated with: right sided (p=0.013), well differentiated (p=0.011), BRAF-wt (p&lt;0.001), PIK3CA-wt (p=0.027) and P53-wt (p=0.002) tumours. A trend was seen between KRAS mutations and female sex (p=0.074) and increased SIG (p=0.072). No association was seen with age, deprivation, smoking, ASA Grade, TNM Stage or EMVI. KRAS mutant status was associated with adverse 3-year CSS (74% versus 82%, p=0.006) and OS (69% versus 78%, p=0.070). For CSS, TNM Stage (HR 2.92, p&lt;0.001), KRAS mutant status (HR 1.64, p=0.050) and Systemic Inflammatory Grade (HR 1.34, p=0.004) were independently prognostic. For OS: age (HR 1.39, p=0.022), TNM Stage (HR 1.50, p=0.016) and SIG (HR 1.25, p=0.005) were independently prognostic. A trend was seen between KRAS mutant status and adverse OS (HR 1.47, p=0.079). Conclusions: The present results show an association between KRAS mutational status and SIG. Furthermore, both of these factors were associated with adverse oncological outcomes. Further investigation into the association between KRAS-mutant status and the local/systemic inflammatory response in TNM I-III colon cancer is warranted. While comprehensive genomic profiling is likely to become increasingly common place, staging the host (SIR) should also be routinely undertaken.